title: The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23.
abstract: Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4(+) and CD8(+) T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle.
  
  
  
  We first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2.
  
  
  
  Thus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines.
authors.affiliation: Institute of Microbiology and Hygiene, Department of Infection Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Weinhold
authors.forename: Martin
authors.initials: M
authors.lastname: Eisenblätter
authors.forename: Edith
authors.initials: E
authors.lastname: Jasny
authors.forename: Michael
authors.initials: M
authors.lastname: Fehlings
authors.forename: Antje
authors.initials: A
authors.lastname: Finke
authors.forename: Hermine
authors.initials: H
authors.lastname: Gayum
authors.forename: Ursula
authors.initials: U
authors.lastname: Rüschendorf
authors.forename: Pablo
authors.initials: P
authors.lastname: Renner Viveros
authors.forename: Verena
authors.initials: V
authors.lastname: Moos
authors.forename: Kristina
authors.initials: K
authors.lastname: Allers
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider
authors.forename: Ulrich E
authors.initials: UE
authors.lastname: Schaible
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Martin E
authors.initials: ME
authors.lastname: Mielke
authors.forename: Ralf
authors.initials: R
authors.lastname: Ignatius
mesh_terms: D018122:B7-1 Antigen / Q000378:metabolism; D002003:Brucella abortus / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D057809:HEK293 Cells; D006680:HLA Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D018122:B7-1 Antigen; D019013:CD40 Antigens; D016207:Cytokines; D006680:HLA Antigens; D006684:HLA-DR Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D053759:Interleukin-23; D016209:Interleukin-8; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D018664:Interleukin-12